First-in-Human, Healthy Volunteers Integrated Protocol of ETC-206, an Oral Mnk 1/2 Kinase Inhibitor Oncology Drug.

In the last decade, drug development has tackled substantial challenges to improve efficiency and facilitate access to innovative medicines. Integrated clinical protocols and the investigation of targeted oncology drugs in healthy volunteers (HVs) have emerged as modalities with an increase in scope and complexity of early clinical studies and first-in-human (FIH) studies in particular. However, limited work has been done to explore the impact of these two modalities, alone or in combination, on the scientific value and on the implementation of such articulated studies.

Drugs' development in acute heart failure: what went wrong?

Acute heart failure (AHF) is a major burden disease, with a complex physiopathology, unsatisfactory diagnosis, treatment and a very poor prognosis. In the last two decades, a number of drugs have progressed from preclinical to early and late clinical development, but only a few of them have been approved and added to a stagnant pharmacological armamentarium. We have reviewed the data published on drugs developed for AHF since early 2000s, trying to recognise factors that have worked for a successful approval or for the stoppage of the program, in an attempt to delineate future trajectories for AHF drug development.

Relationship between ketamine-induced psychotic symptoms and NMDA receptor occupancy: a [(123)I]CNS-1261 SPET study.

Rationale: Ketamine induces effects resembling both positive and negative psychotic symptoms of schizophrenia. These are thought to arise through its action as an uncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor.

Objectives: We used [(123)I]CNS-1261 to study ketamine binding to NMDA receptors in healthy human controls in vivo and its relationship to positive and negative psychotic symptom induction.

Effect of sustained-release (SR) bupropion on craving and withdrawal in smokers deprived of cigarettes for 72 h.

Rationale: Sustained-release (SR) bupropion enhances quit rates of smokers, generally decreases tobacco withdrawal, and in some studies, reduces craving.

Objective: Investigate the effects of SR bupropion on craving and withdrawal during cigarette abstinence.

Methods: Twenty three smokers participated in three 17-day periods composed of 14 out-patient days followed by 3 (72 h) in-patient days.

EEG power spectra and auditory P300 during free smoking and enforced smoking abstinence.

We investigated resting EEG and auditory P300 during free smoking and 36 h of enforced smoking abstinence in 12 healthy volunteers. Resting EEG was recorded on 19 scalp leads and auditory P300 was obtained by an oddball paradigm task. Spectral analysis of EEG (absolute and relative power, mean frequency), latency and amplitude of auditory P300 were considered for statistical analysis.

Quantitative cerebral H2(15)O perfusion PET without arterial blood sampling, a method based on washout rate.

The quantitative determination of regional cerebral blood flow (rCBF) is important in certain clinical and research applications. The disadvantage of most quantitative methods using H(2)(15)O positron emission tomography (PET) is the need for arterial blood sampling. In this study a new non-invasive method for rCBF quantification was evaluated.

Smokers deprived of cigarettes for 72 h: effect of nicotine patches on craving and withdrawal.

Rationale: Research on the effects of nicotine abstinence and nicotine replacement has not provided consistent information about the impact of replacement therapies on tobacco withdrawal and craving.

Objective: . This study investigated craving and withdrawal symptoms over a 72-h period of abstinence from cigarettes.

Correlation and predictive performances of saliva and plasma nicotine concentration on tobacco withdrawal-induced craving.

Aims: To investigate whether saliva is a useful alternative to plasma for routine monitoring of nicotine and evaluate the predictive performances of saliva and plasma concentration on craving estimated by a Tiffany Questionnaire on Smoking Urge-Brief Form.

Methods: Thirteen healthy smokers were enrolled in a randomized, two period, crossover trial. Linear and power models were evaluated to predict the plasma nicotine concentrations from the saliva measurements, whereas a population PK/PD indirect response model was used to predict craving using either saliva or plasma nicotine concentration as the independent variable.

Absolute quantification of cerebral blood flow with magnetic resonance, reproducibility of the method, and comparison with H2(15)O positron emission tomography.

While H2(15)O positron emission tomography (PET) is still the gold standard in the quantitative assessment of cerebral perfusion (rCBF), its technical challenge, limited availability, and radiation exposure are disadvantages of the method. Recent work demonstrated the feasibility of magnetic resonance (MR) for quantitative cerebral perfusion imaging. There remain open questions, however, especially regarding reproducibility.